The 'metabolic syndrome of aging' in this Program refers to a constellation of metabolic defects including insulin resistance, abdominal obesity, dyslipidemia, hypertension and increased circulating levels of pro-thrombotic and pro-inflammatory peptides. This syndrome is an important risk factor for cardiovascular disease and other age-related diseases, with significant impact on all-cause mortality. We hypothesize that aging is characterized by a decline in hypothalamic function leading to a relative or absolute increase in energy intake, increased fat mass and impaired regulation of fat distribution. We propose that the resulting increases in nutrient availability, total adiposity and abdominal fat distribution contribute both independently and cooperatively to the metabolic syndrome of aging. The hexosamine biosynthetic pathway (HBP) may provide a unifying role as a 'nutrient-sensing' pathway, since its activation by nutrient excess results in functional alterations of key intracellular proteins by glycosylation. Activation of the HBP in fat and endothelial cells induces the expression of pro-thrombotic and pro-inflammatory peptides, which may contribute to insulin resistance and endothelial dysfunction. Increased fat mass, and selective increases in the metabolically dangerous abdominal fat, would therefore potentiate the above process. The overall long-term goals of this Program Project are: 1. To demonstrate that excess nutrients can initiate the key components of the metabolic syndrome of aging. 2. To implicate specific nutrient-sensing pathways in the pathophysiology of this syndrome. 3. To develop new therapeutic approaches for the protection from age-related diseases. These goals will be pursued by a team of investigators at the Albert Einstein College of Medicine. These investigators have an extensive history of collaboration, and their laboratories and offices are contiguous. This program spans the full spectrum from cell biology to in vivo animal physiology to 'translational' studies in humans. Finally, 3 cores will provide all projects with administrative assistance and standardized common measurements (Gene Expression and Protein Chemistry/Animal Physiology Cores) linking the activation of nutrient-sensing pathways with gene expression and plasma levels of key peptides.